Optical Resolution of a 1, 5-Benzothiazepine Derivative, a Synthetic Intermediate of Diltiazem, by Preferential Crystallization and Diastereomeric Salt Formation

Abstract

Practical preparation methods of an optically active intermediate of diltiazem, (+)-(2S, 3S)-5-[2-(dimethylamino)ethyl]-2, 3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1, 5-benzothiazepin-4(5H)-one [(+)-7], have been developed by the use of physicochemical and chemical resolutions. 1) The salt of (±)-7 with 3-amino-4-hydroxy-benzenesulfonic acid (AHS), was found to exist as a conglomerate and could be reproducibly resolved into (+)-7·AHS and (-)-7·AHS of 94-98% ee by a preferential crystallization procedure. 2) (+)-(1R)-3-Bromocamphor-9-sulfonic acid [(+)-BCS] was found to be an efficient resolving agent for (±)-7 and the diasteoremeric resolution provided (+)-7·(+)-BCS·2H₂O salt in >43% yield and >97% ee by fractional crystallization. It is presumed that the crystal water of (+)-7·(+)-BCS·2H₂O plays an important role in the selective crystallization during this efficient resolution.